Mechanism of Action:

• CGRP antagonists (gepants) block the calcitonin gene-related peptide (CGRP) receptor, preventing CGRP-mediated vasodilation and neurogenic inflammation, which are key contributors to migraine pathophysiology.
• Rationale: CGRP is a potent vasodilator and pro-inflammatory neuropeptide implicated in migraine.

• Classes of CGRP Antagonists:
  • Small-molecule antagonists (gepants):
    • Ubrogepant: Approved for acute migraine treatment (25–100 mg PO).
    • Rimegepant: Approved for both acute (75 mg PO) and preventive (75 mg PO daily) migraine treatment.
    • Atogepant: Approved for migraine prevention (10–60 mg PO daily).
  • Monoclonal antibodies (mAbs):
    • Erenumab: Targets the CGRP receptor (70–140 mg SC monthly).
    • Fremanezumab: Targets CGRP (225 mg SC monthly or 675 mg quarterly).
    • Galcanezumab: Targets CGRP (120 mg SC monthly; 240 mg loading dose).
    • Eptinezumab: Targets CGRP (100 mg IV quarterly; 300 mg loading dose).

• Efficacy:
  • Acute treatment: Gepants (e.g., ubrogepant, rimegepant) achieve pain freedom in ~20–30% of patients at 2 hours, with ~50–60% achieving pain relief.
  • Preventive treatment: Gepants (e.g., atogeppant) reduce monthly migraine days by ~4–5 days, with mAbs (e.g., erenumab) reducing by ~2–4 days.
  • Rationale: CGRP antagonism disrupts the migraine cascade, offering a targeted approach with fewer systemic side effects than triptans.

• Adverse Effects:
  • Gepants: Mild (e.g., nausea, somnolence) and rare serious effects (e.g., liver enzyme elevation).
  • mAbs: Local injection-site reactions (e.g., erythema, pain) and constipation (erenumab).
  • Rationale: Gepants have a favorable side effect profile due to their receptor specificity, while mAbs may cause systemic reactions due to their immunogenicity.

• Special Considerations:
  • Pregnancy: mAbs are not recommended due to limited safety data; gepants are less attractive for females of reproductive age due to potential teratogenicity.
  • Cardiovascular disease: Gepants are preferred over triptans due to lower vasoconstrictive risk.
  • Rationale: CGRP antagonism avoids the vasoconstrictive risks of triptans, making it safer for patients with cardiovascular comorbidities.

• Guidelines:
  • AHS/ANM: Recommend CGRP antagonists as first-line preventive options for patients with chronic migraine or contraindications to other preventives.
  • EHMTIC: Suggests gepants as an alternative to triptans for acute treatment in patients with cardiovascular risk factors.
  • Rationale: Guidelines reflect the growing evidence supporting CGRP antagonism as a safe and effective option for migraine management.

• Emerging Data:
  • Preventive use of gepants: Atogepant (60 mg PO daily) reduced monthly migraine days by ~5 days in the PROGRESS trial (Lancet Neurol 2020; 19:727).
  • Blurred distinction: Gepants’ dual acute/preventive role challenges the traditional separation of migraine treatments.
  • Rationale: Emerging data support the versatility of CGRP antagonists in migraine management.